Device and method for the transdermal delivery of cannabidiol

ABSTRACT

Transdermal delivery devices for the delivery of cannabidiol (CBD) are shown and described. In a reservoir-patch design, a microporous, hydrophilic membrane and a backing define a reservoir that houses a mixture of CBD, a polar liquid, and a gelling agent. The hydrophilic membrane is coated with an amine-compatible silicone skin adhesive. In a monolithic design, a release liner is coated with a mixture of CBD and a PIB or amine-compatible silicone skin adhesive laminated to the hacking material. In either design, the CBD may be provided as a pure compound or as a component of a cannabis oil.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. patent application Ser. No15/172,365, filed Jun. 3, 2016, which claims the benefit of U.S.Provisional Patent Application No. 62/172,920, filed Jun. 9, 2015, theentirety of which is hereby incorporated by reference.

BACKGROUND

Cannabidiol (CBD, C21H3002, CAS Registry No. 13956-29-1) is an activecannabinoid present in Cannabis, a genus of flowering plants thatincludes Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Othercannabinoids include tetrahydrocannabinol (THC), tetrahydrocannabinolicacid (THC-a), cannabinol (CBN), and cannabichromene (CBC).

CBD and THC-a are main components of the marijuana plant. For decades,the CBD content in marijuana plants was very low (below 5%), and allefforts were directed toward increasing the content of psychoactivecomponent of marijuana—THC—for recreational purposes. Recently however,extensive medical research of medicinal attributes of marijuana suggeststhat CBD is the most important a non-psychoactive component of marijuanathat possesses a wide range of therapeutic benefits.

Growers of marijuana developed new strands of the plant with highcontent of CBD. When subjected to an extraction process the yield of CBDin the concentrated extract (oil, shatters) may approach 70% by weightand higher. The increased CBD concentration made it possible toformulate products consumed as edibles, tinctures capsules, lotions, andcreams containing medicinal quantities of CBD. The CBD in such productshas been used for serious therapeutic medical treatments such as:reversing alcohol induced brain damage, treating of severe socialanxiety, turning off the cancer gene found in metastasis, effectivelytreating schizophrenia and epilepsy, treating neurogenerative disordersor even slowing down Parkinson's disease and Alzheimer's disease.

Successful use of CBS for medical treatments such as the foregoingdepends on the dose of the medicine, reducing side effects, and patientcompliance. Orally taken CBD is exposed to the gastric environment andliver, which metabolizes the medicine and thereby lowers itsbioavailability. Creams and lotions act for a short time being rubbedoff by cloth and washed off

Transdermal delivery is an alternate route for delivering potentmedicines. It circumvents the gastric system, and therefore, the medicalsubstance does not cause liver damage and has increased bioavailability.In particular, children are most susceptible to such damage and mayparticularly benefit from the transdermal delivery of CBD becausetransdermal delivery allows for the controlled, sustained delivery ofCBD to the body for at least 24 hrs—and possibly for 2-3 days—withoutdamaging young livers.

Transdermal delivery of cannabinoids has been proposed. However, knownreservoir-style transdermal devices have used liquid carriers and/orhydrophobic rate-controlling membranes and carriers which haveundesirably limited the rate of mass transfer of CBD through the skin.In addition, certain known reservoir-style devices require an additionaladhesive coated overlay to hold the device in place on the wearer'sskin.

Monolithic transdermal devices (also known as “drug-in-adhesive”devices) for delivering cannabinoids have also been proposed. However,the adhesive used in such known devices has typically limited the rateof mass transfer of CBD to the skin.

Thus, a need has arisen for a transdermal device for delivering CBD.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a side cross-sectional view of a reservoir-style transdermaldevice for delivering CBD to a wearer's skin;

FIG. 2 is a side cross-sectional view of a monolithic-style transdermaldevice for delivering CBD to a wearer's skin;

FIG. 3 is a graph depicting the cumulative flux (pg/cm²) of CBD withrespect to time (hours) through a human cadaver epidermis from asolution comprising ten (10) percent by weight CBD and 90 percent byweight of an ethanol solvent through each of a hydrophilic, microporousmembrane and a hydrophobic, microporous membrane;

FIG. 4 is a graph depicting the cumulative flux (μg/cm²) of CBD withrespect to time (hours) through a human cadaver epidermis through adevice with a hydrophilic, porous membrane and a device lacking such amembrane from a solution comprising five (5) percent by weight of CBDand 90 percent by weight of a solvent comprising 70 percent by weightethanol and 30 percent by weight water;

FIG. 5 is a graph depicting the cumulative flux (μg/cm²) of CBD througha human cadaver epidermis over a six hour period from solutionscomprising ten (10) percent by weight CBD and 90 percent by weight ofone of three liquid carriers;

FIG. 6 is a graph depicting the cumulative flux (μg/cm²) of CBD througha human cadaver epidermis over a six hour period from solutionscomprising ten (10) percent by weight CBD and 90 percent by weight ofone of four liquid carriers;

FIG. 7 is a graph depicting the cumulative flux (μg/cm²) of CBD througha human cadaver epidermis from a monolithic adhesive matrix comprisingvarying amounts (weight percent) of three different adhesives andvarying amounts (weight percent) of pure CBD; and

FIG. 8 is a graph depicting the cumulative flux (μg/cm²) of CBD througha human cadaver epidermis from a monolithic adhesive matrix comprisingvarying amounts (weight percent) of three different adhesives and 25percent by weight of a cannabis oil comprising 45.3 percent by weightCBD and 33.5 percent by weight THC.

DETAILED DESCRIPTION

Described below are examples of transdermal delivery devices fordelivering CBD through the epidermis of a wearer of the device. Bothreservoir-style, and monolithic-style devices are described. In thereservoir style device, a reservoir comprising a solution of CBD (whichmay be present as substantially pure CBD or an oil extract of a cannabisplant which comprises CBD and other cannabinoids) and a liquid carrieris provided and is defined between a hydrophilic, porous membrane and abacking. One side of the hydrophilic, porous backing is coated with askin adhesive that is covered with a release liner. To use the device,the user removes the release liner and contacts the skin adhesive-sideof the membrane with the skin to affix the device to the body. Preferredskin adhesives include amine-compatible, silicone adhesives. The phrase“amine-compatible” refers to the fact that the adhesive is substantiallynon-reactive with amines. Many drugs are amines that bond with hydrogendonors. Silicone adhesive polymers typically have OH groups that arehydrogen donors. When mixed with drugs that have NH groups (amines) orOH groups (like cannabidiol) that can accept hydrogen, the drug andsilicone polymer will bond through hydrogen bonding, which retards thediffusion of drug molecules from the adhesive matrix. To avoid thatdiffusion retardation, the OH groups of the silicone polymer, are cappedwith methyl groups. Such silicone adhesive will be called “aminecompatible” which means they are essentially chemically neutral.

The CBD diffuses through the hydrophilic porous membrane and the skinadhesive and into the user's skin.

In a first monolithic-style device, a skin adhesive is mixed with theCBD (which may be present as substantially pure CBD or an oil extract ofa cannabis plant which comprises CBD and other cannabinoids) to define asubstantially monolithic mixture of adhesive and CBD. The skin adhesiveis coated on a backing that is preferably occlusive. The skin adhesiveis preferably an amine-compatible silicone adhesive.

In a second monolithic-style device, a skin adhesive is mixed with theCBD (which may be present as substantially pure CBD or an oil extract ofa cannabis plant which comprises CBD and other cannabinoids) to define asubstantially monolithic mixture of adhesive and CBD. The skin adhesiveis preferably a polyisobutylene adhesive having a viscosity-averagemolecular weight ranging from about 30,000 Daltons to about 70,000Daltons, preferably, from about 35,000 Daltons to about 65,000 Daltons,and more preferably from about 40,000 Daltons to about 60,000 Daltons.

Referring to FIG. 1, a reservoir-style transdermal delivery device 20for the transdermal delivery of CBD is depicted. Reservoir-styletransdermal delivery device 20 comprises a backing 22 and a hydrophilic,porous membrane 24. The backing 22 and hydrophilic, porous membrane 24are attached to one another so as to define a closed volume which actsas a reservoir 26. A preparation 27 comprising CBD, a liquid carrier,and a gelling agent is disposed in the reservoir 26. First side 34 ofthe hydrophilic, porous membrane 24 is in contact with the preparation27. A second side 36 of the hydrophilic, porous membrane 24 faces awayfrom backing 22 and is coated with a skin adhesive 30. The skin adhesive30 is preferably formulated to adhere the device 20 to the user's skinfor a period of no less than about 24 hour's while avoiding appreciableskin irritation to the user's skin. Preferred skin adhesives 30 includeamine-compatible, silicone, pressure sensitive adhesives. In certainexamples, an amine-compatible silicone skin adhesive 30 is providedwhich comprises a trimethylsiloxy end-capped reaction product of asilanol end-blocked polydimethylsiloxane and a silicate resin. The skinadhesive is preferably provided as an organic solvent solutioncomprising from about 50 percent to about 70 percent by weight of solidadhesive in an organic solvent like heptane or ethyl acetate and havinga viscosity at 20° C. of from about 400 mPa-s to about 1300 mPa-s,preferably from about 450 mPa-s to about 1250 mPa-s, and more preferablyfrom about 500 mPa-s to about 1200 mPa-s.

A first surface 29 of a release liner 28 is releasably adhered to skinadhesive 30, and a second surface 31 of release liner 28 faces away fromskin adhesive 30. Suitable release liners include occlusive polymericfilms, such as polyester, polypropylene, coated with a release coatingthat is releasably adherable to silicone, polyisobutylene, and siliconeadhesives. Suitable release coatings on first surface 29 of releaseliner 28 include fluoropolymers and silicone polymers.Commercially-available, coated release liners that are suitable for useas release liner 28 include Scotchpak 1022, 9741, 9744, 9748, and 9755supplied by 3M of Minneapolis, Minn., and FRA 314 and 315 supplied byFox River Co. To use the reservoir transdermal device 20, release liner28 is peeled away from skin adhesive 30, thereby exposing skin adhesive30, and the device 20 is applied so that the skin adhesive 30 contactsthe user's skin.

Suitable examples of such amine-compatible silicone adhesives includethe BIO-PSA 7-4301 and 7-4302 skin adhesives supplied by Dow Corning.BIO-PSA 7-4301 is a high tack, amine-compatible silicone adhesive inheptane available with a solids content of 60 percent and 70 percent andcorresponding viscosities at 20° C. of 450 mPa-s and 1600 mPa-s. BIO-PSA7-4302 is a high tack, amine-compatible silicone adhesive in ethylacetate with a solids content of 60 percent by weight and a viscosity of1200 mPa-s at 20° C. The skin adhesive 30 is coated to a thickness perunit area on the membrane 24 that is preferably from about 10 to about20 g/m², more preferably from about 12-18 g/m², and still morepreferably from about 14-16 g/m².

Hydrophilic, porous membrane 24 preferably has a mean flow pore size ofno more than about 1 micron, preferably not more than about 0.8 microns,still more preferably no more than about 0.4 microns, and even morepreferably no more than about 0.2 microns. At the same time, porousmembrane 24 preferably has a mean flow pore size of no less than about0.02 microns, more preferably no less than about 0.04 microns, stillmore preferably no less than about 0.06 microns, and even morepreferably no less than about 0.08 microns. The mean flow pore size maybe determined in accordance with the method set forth at page 17, line22 to page 18, line 4 of published PCT Application WO2010072233, theentirety of which is hereby incorporated by reference.

In the same or other examples, hydrophilic porous membrane 24 preferablyhas a porosity of at least about 60 percent, more preferably at leastabout 65 percent, and still more preferably at least about 70 percent.At the same time, hydrophilic porous membrane 24 preferably has aporosity of no more than about 90 percent, more preferably no more thanabout 85 percent, and still more preferably no more than about 80percent. Porosity values may be calculated as described at page 7, lines24 to 27 of WO2010072233.

In the same or other examples, hydrophilic porous membrane 24 preferablyhas a thickness of no more than about 50 microns, preferably no morethan about 40 microns, and even more preferably no more than about 35microns. At the same time, hydrophilic porous membrane 24 preferably hasa thickness of no less than about 10 microns, more preferably no lessthan about 20 microns, and still more preferably no less than about 25microns. Membrane thicknesses may be determined as described at page 18,lines 19-21 of WO2010072233.

In the same or other examples, hydrophilic porous membrane 24 preferablyhas an air permeability as determined by the Gurley Test Method(according to ISO 5636-5) that is preferably at least about 10 sec/50ml, more preferably at least about 20 sec/50 ml, and still morepreferably at least about 25 sec/50 ml. At the same time, hydrophilicporous membrane 24 preferably has an air permeability of no more thanabout 50 sec/50 ml, more preferably no more than about 40 sec/50 ml, andstill more preferably no more than about 35 sec/50 ml.

In the same or other examples, hydrophilic porous membrane 24 preferablyhas a tensile strength in the machine direction as determined by ASTMD882-12 that is preferably at least about 10 MPa, more preferably atleast about 15 MPa, and still more preferably at least about 20 MPa. Inthe same or other examples, the hydrophilic porous membrane 24preferably has a percent elongation in the machine direction asdetermined by ASTM D882-12 that is preferably at least about 10 percent,more preferably at least about 15 percent, and still more preferably atleast about 20 percent.

Hydrophilic porous membrane 24 preferably comprises at least onepolymeric material. In one example, hydrophilic porous membrane 24comprises a polyolefin polymer and a hydrophilic component thatcomprises a hydrophilic polymer and optionally, a surfactant. As usedherein, the term “hydrophilic” when used to describe a porous membranerefers to a membrane that at 20° C. provides a water flux fordemineralized water through the membrane of at least 0.5 liters/(m²hbar).

The content of the polyolefin polymer is preferably less than or equalto 98 percent by weight based on the total dry weight of the membrane24, and the content of the hydrophilic component(s) is preferably atleast 2 weight percent based on the total dry weight of the membrane. Incertain preferred examples, the membrane is formed by combining thepolyolefin polymer with the hydrophilic components(s) and optionaladditives with a solvent to form a blend in the form of a gel, asolution, or a homogeneous mixture, followed by extruding the blend.Suitable polyolefins (such as polyethylene), hydrophilic components, andadditives are described in WO2010072233.

One example of a commercially available hydrophilic, porous membranethat is suitable for use as hydrophilic, porous membrane 24 is suppliedby Lydall Performance Materials B.V. under the name Evopor™ 5E02A.Evopor™ 5E02A is a porous hydrophilic membrane comprising a polyethylenesupport and a poly (ethyl vinyl) alcohol hydrophilic component.

As mentioned previously, preparation 27 comprises CBD and a liquidcarrier. In certain examples, the polar organic liquid comprises amolecule having one or more carboxylic acid groups. In the same or otherexamples, the polar organic liquid comprises a molecule having one ormore hydroxyl groups. Suitable polar organic liquids comprising one ormore hydroxyl groups include those comprising between 2 and 30 carbonatoms per molecule, including without limitation, ethanol. Suitablepolar organic liquids comprising one or more carboxylic acid groupsinclude fatty acids, including without limitation oleic acid. Liquidcarriers comprising ethanol and/or oleic acid are preferred, and liquidcarriers comprising oleic acid are especially preferred. Suitable liquidcarriers also include mixtures of polar organic liquids and water.Examples of such mixtures include mixtures of ethanol and water. Inethanol/water mixtures, the maximum concentration of water is preferablyabout ten (10) percent by weight of the total amount of ethanol andwater.

Preparation 27 also may comprises a gelling agent which makes thepreparation thixotropic. Suitable gelling agents include: sodiumcarboxymethyl cellulose, hydroxypropyl cellulose, hydroxyethylcellulose, polyacrylic acid, methyl cellulose, xantam gum, etc. Incertain examples, cellulose gelling agents such as hydroxyethylcelluloseare preferred. The gelling agent increases the viscosity of and providesstructural integrity to preparation 27, which improves the ease ofplacing and retaining preparation 27 in reservoir 26 before thereservoir 26 is closed by heat sealing the hydrophilic, porous membrane24 to the occlusive backing 22. The gelling agent is preferablypharmacologically inactive.

The CBD is present in a therapeutically effective amount in preparation27. A “therapeutically effective amount” is an amount of CBD sufficientto achieve a desired therapeutic effect over a desired time period. TheCBD may be provided as substantially pure CBD, such as in a powder form,or as part of an oil extract comprising other cannabinoids. Presently(2015) marijuana growers extract CBD from plants in form of oils or“shatters” that have content of CBD ranging fern 25 to 80% by weight ofthe oil and THC from 10-25% by weight of the oil. Recently, however, dueto availability of sophisticated separators, it made possible to obtainpure CBD of 99.9% from hybrid marijuana plants or hemp plans with verylow content of THC below 0.1%.

In certain examples, preparation 27 preferably comprises from about one(1) percent to about fifty (50) percent by weight CBD, more-preferablyfrom about five (5) to about 30 percent by weight CBD, and morepreferably from about 10 to about 20 percent by weight CBD.

In the same or other examples, the preparation 27 comprises a liquidcarrier in amounts ranging from about 50 percent to about 99 percent byweight of the preparation 27. Preparation 27 also comprises from aboutone (1) percent to about ten (10) percent, and preferably about three(3) percent of a gelling agent (preferably hydroxyl propyl cellulose) byweight of the preparation 27. Preparation 27 also includes from zero toabout ten (10) percent by weight of at least one penetration enhancer.In certain examples, the liquid carrier comprises at least one polarliquid of the type described previously. Suitable penetration enhancersinclude 1,2 propylene glycol, dimethyl sulfoxide (DMSO), oleic acid, andisopropyl palmitate (IPP).

When provided as substantially pure CBD, the amount of CBD inpreparation 27 by weight of CBD plus liquid carrier(s) (i.e., excludinggelling agents such as cellulose derivatives like hydroxyl propylcellulose), preferably ranges from about two (2) percent to about 40percent by weight of the combination of CBD and liquid carrier(s) morepreferably from four (4) percent to about 30 percent by weight of thecombination of CBD and liquid carrier(s), and still more preferably fromabout five (5) percent to about 20 percent by weight of the combinationof CBD and liquid carrier(s). When CBD is provided as part of a cannabisplant oil extract, the concentration of oil in the combination of oiland liquid carrier(s) is preferably from about five (5) percent toabout, fifteen (15) percent by weight of the combination of oil andliquid carrier(s), more preferably from about eight (8) percent to aboutthirteen (13) percent by weight of the combination of oil and liquidcarrier(s), and still more preferably from about nine (9) to abouteleven (11) percent by weight of the combination of oil and liquidcarriers(s). Ten percent oil by weight of the combination of oil andliquid carrier(s) is especially preferred.

Suitable backing materials for backing 22 include occlusive polymericfilms such as polyethylene, polyethylene terephthalate (PET) andcombinations thereof. Although device 20 may include an overlay patch,in preferred examples, one is not provided. In general, an overlay patchis not necessary if the hydrophilic, porous membrane 24 is alreadycoated with skin adhesive 30. If the membrane 24 is not coated with anadhesive (e.g., in order to maximize the flux of CBD into the skin), anoverlay patch should be placed over the reservoir 26 in order to ensureintimate contact of the hydrophilic, porous membrane 24 with skin. Incertain examples, the skin contact area (“active transdermal flux area”)of the membrane 24 of a device 20 is preferably at least about 10 cm²,more preferably at least about 20 cm² and still more preferably at leastabout 30 cm². At the same time, the skin contact area of device 20 ispreferably no more than about 30 cm², preferably no more than about 25cm² and still more preferably no more than about 22 cm². At a given fluxrate, the skin contact area may be selected to achieve the desired dailydose of CBD (or the dose over whatever time period is of therapeuticinterest).

Referring to FIG. 2, an example of monolithic-style transdermal drugdelivery device 40 for delivering CBD is depicted. Monolithictransdermal device 40 includes a backing 42 of the type describedpreviously with respect to backing 22 of reservoir transdermal device20. A matrix 44 of skin adhesive mixed with a therapeutically effectiveamount of CBD is coated on one side of backing 42. The matrix 44 ispreferably formulated to adhere the device 20 to the user's skin for aperiod of no less than about 24 hours while avoiding appreciable skinirritation to the user's skin. A release liner 48 is releasable adheredto matrix 44 on a surface of matrix 44 opposite the surface adhered tobacking 42. First side 49 of release liner 48 faces away from matrix 44and a portion of second side 51 of release liner 48 is adhered to matrix44. To use the monolithic transdermal device 40, the release liner 48 ispeeled away and the exposed surface of adhesive matrix 44 is applied tothe skin.

The skin adhesive comprising matrix 44 preferably comprises at least oneof an acrylate pressure sensitive adhesive, a polyisobutylene pressuresensitive adhesive, and an amine-compatible silicone pressure sensitiveadhesive. Suitable acrylate adhesives include DuroTak 87-2516. Suitablepolyisobutylene adhesives include those having a viscosity-averagemolecular weight ranging from about 30,000 Daltons to about 70,000Daltons, preferably from about 35,000 Daltons to about 65,000 Daltons,and more preferably from about 40,000 Daltons to about 60,000 Daltons.Suitable polyisobutylene adhesives also have a viscosity at 20° C.ranging from about 1000 mPa-s to about 3000 mPa-s.

In certain preferred examples, matrix 44 preferably comprise apolyisobutylene adhesive having a viscosity-average molecular weight asdescribed above and an adhesion/viscosity modifier. Theadhesion/viscosity modifier is preferably a mineral oil or siliconefluid present in an amount ranging from about one (1) to about ten (10)percent by weight of matrix 44, more preferably from about two (2) toabout six (6) percent by weight of matrix 44, and still more preferablyfrom about three (3) to about four (4) percent by weight of the matrix44. Mineral oils that are suitable for use as the adhesion/viscositymodifier have a molecular weight ranging from 100 to about 1000 Daltons,more preferably from about 200 to about 600 Daltons, even morepreferably from about 350 Daltons to about 450 Daltons, and still morepreferably about 400 Daltons. Silicone fluids that are suitable for useas the adhesion/viscosity modifier preferably comprise —OH end-cappedpolydimethylsiloxanes having a kinematic viscosity at 20° C. rangingfrom about 100 cSt to about 1000 cSt. Commercially available siliconefluids that may be used as the adhesion/viscosity modifier include theDow Corning Q7-9120 fluids, which are available in kinematic viscosities(at 20° C.) of 20, 100, 350, 1000, and 12,500 cSt. In preferred examplesof silicone adhesion/viscosity modifier, the Q7-9120 100 cSt or 1000 cStfor mixtures thereof) are used.

Preferred polyisobutylene adhesives are not supplied with mineral oil.In certain preferred examples, the polyisobutylene component of matrix44 is a Vistanex LM polyisobutylene adhesive. In other preferredexamples, the polyisobutylene component of matrix 44 is an Oppanol B13polyisobutylene adhesive supplied by BASF.

In yet another example, the adhesive component of matrix 44 may comprisea blend of acrylic adhesive and polyisobutylene adhesive, andpreferably, a blend of an acrylic adhesive and a polyisobutyleneadhesive having the viscosity-average molecular weight described above(from about 30,000 Daltons to about 70,000 Daltons, preferably fromabout 35,000 Daltons to about 65,000 Daltons, and more preferably fromabout 40,000 Daltons to about 60,000 Daltons). When acrylic adhesivesare combined with such polyisobutylene adhesives, the amount of acrylicadhesive by weight of the total amount of adhesive in matrix 44 ispreferably from about one (1) to about 50 percent. In one example, theadhesive component of matrix 44 comprises 80 percent Oppanol B13 byweight of the total amount of adhesive in matrix 44 and twenty (20)percent Durotak 87-2516 by weight of the total amount of adhesive inmatrix 44.

In examples in which matrix 44 comprises an amine-compatible siliconeadhesive, the amine-compatible silicone adhesive is preferably of thetype described previously with respect to skin adhesive 30 of reservoirtransdermal device 20.

The amount of CBD in the matrix 44 preferably ranges from about one (1)to about 30 percent by weight of the matrix 44, more preferably fromabout two (2) percent to about 25 percent by weight of the matrix 44,and still more preferably from about five (5) percent to about twenty(20) percent by weight of the matrix 44. The amount of cannabiscompounds other than CBD is preferably less than about one (1) percent.In those cases where pure CBD is used in matrix 44, the amount of pureCBD by weight of matrix 44 is preferably from about two (2) percent toabout twenty (20) percent, more preferably from about four (4) percentto about fifteen (15) percent, and still more preferably from about five(5) percent to about ten (10) percent.

When CBD is provided as part of a cannabis plant oil extract, the amountof oil by weight of matrix 44 is preferably from about fifteen (15)percent to about 40 percent by weight, preferably from about twenty (20)percent to about 30 percent by weight, and still more preferably fromabout 24 percent to about 26 percent by weight in such cases, the CBDcontent as a percentage of the cannabis plant oil extract is preferablyfrom about 25 percent to no more than about 50 percent, more preferablyfrom about 30 percent to about 50 percent, and still more preferablyfrom about 40 percent to about 50 percent by weight of the cannabis oil.

In certain preferred examples wherein CBD is provided as part of acannabis plant oil extract, the oil further comprises rosins and/orterpenes that remain present after extraction. It has been found thatthese rosins and terpenes improve adhesion to the skin. Thus, the use ofplant extract oils in monolithic device 40 provides a synergistic effectin both allowing for transdermal delivery of CBD and providing a device40 that can withstand showers and minor brushings over the worn device40 for many days.

Monolithic device 40 may also include penetration enhancers, includingbut not limited to oleic acid, isopropyl palmitate (IPP), DMSO, 1,2propylene glycol, and isopropyl myristate (IPM). The amount ofpenetration enhancer preferably ranges from zero to about ten (10)percent by weight of the matrix 44.

In certain examples, the skin contact area of device 20 is preferably atleast about 10 cm², more preferably at least about 15 cm², and stillmore preferably at least about 18 cm². At the same time, the skincontact area of device 20 is preferably no more than about 30 cm²,preferably no more than about 25 cm² and still more preferably no morethan about 22 cm². At a given flux rate, the skin contact area may beselected to achieve the desired daily dose of CBD (or the dose overwhatever time period is of therapeutic interest).

EXAMPLE 1

The effects of using a hydrophobic, porous membrane versus ahydrophilic, porous membrane (such as membrane 24) in reservoirtransdermal device 20 are studied in this example. A mixture is formedby dissolving CBD powder in ethanol to yield a solution comprising 10percent by weight CBD and 90 percent by weight ethanol. The backing 22is an occlusive backing film (PE/PET from 3M). Hydroxy ethyl celluloseis added to the solution to yield a thixotropic preparation 27. A volumeof 300 μL of the preparation is placed in the reservoir 26.

The skin adhesive 30 is a BIO PSA 7-4301 adhesive coated to a thicknessof 15 g/m²on side 36 of membrane 24. An overlay adhesive patch is placedover the reservoir which forms an island in the middle. The overlayassures adhesion of the reservoir to the skin. The device 20 iscontacted with a human cadaver epidermis, and diffusion through theepidermis is measured using the Franz Diffusion Cell method.

In a first run, membrane 24 is a Lydall® Evopor™ 5E02A, hydrophilic,microporous membrane (of 0.2 μm pore size). In a second run, the device20 is constructed similarly, but membrane 24 is a hydrophobic Lydall®Solupor™ 7P03A porous membrane. As FIG. 3 indicates, after a period ofabout 9 hours, the device 20 with the hydrophilic membrane provides amonotonically increasing cumulative flux of CBD through the cadaver skinwhich significantly exceeds the cumulative flux of CBD from thehydrophobic membrane device, which becomes asymptotic at about 300μg/cm².

EXAMPLE 2

The reservoir device 20 of Example 1 is used, but instead of usingethanol alone as the liquid carrier, a mixture of ethanol and water isused wherein the ethanol comprises 70 percent by weight of theethanol/water mixture, and water comprises 30 percent by weight of theethanol/water mixture. The amount of CBD by weight of the combination ofCBD and ethanol/water is 5 percent, and the amount of ethanol/water is91.5 percent. The gelling agent is hydroxyethylcellulose, which ispresent in an amount of about 3.5% by weight of the preparation 27. Afirst run is conducted in which the membrane is placed comprises CBD ispresent.

The device 20 is contacted with a human cadaver epidermis, and diffusionthrough the epidermis is measured using the Franz Diffusion Cell method.In a first run, the hydrophilic, porous membrane 24 of Example 1 isused. In a second run, the membrane 24 is omitted so that CBD diffusesdirectly through the skin adhesive 30. The cumulative flux versus timeis plotted in FIG. 4, which indicates that the permeability of CBDthrough the skin is the same regardless of whether the membrane 24 isprovided. It is also discovered that an overlay patch (not shown inFIG. 1) is not required to hold device 20 on the skin.

EXAMPLE 3

This example is conducted using three reservoir transdermal devices suchas those of Example 1, with each having the hydrophilic, porous membranedescribed therein. In each case, the preparation includes a mixture ofCBD and a liquid carrier with ten (10) percent CBD by weight of theCBD/liquid carrier mixture. Three runs are conducted, each with a devicethat includes a different liquid carrier in its preparation 27: 1,2propylene glycol, PEG-300, and oleic acid. Diffusion through a humancadaver epidermis is measured using the Franz Diffusion Method.

The cumulative flux versus time is plotted in FIG. 5. As the figureindicates, throughout the period, oleic acid provides a significantlybetter rate of transfer of CBD through the skin than either 1,2propylene glycol or PEG-300.

EXAMPLE 4

This example is similar to Example 3, except that an ethanol carrier isalso tested. As indicated in FIG. 6, ethanol shows superior transfer ofCBD through the skin relative to 1,2 propylene glycol and PEG-300.However, oleic acid provides superior transfer relative to all three ofthe other liquid carriers.

EXAMPLE 5

A monolithic transdermal device 40 is constructed using a matrix 44 ofpure CBD and three different adhesives. A first device 40 includes aPE/PET backing and a matrix 44 comprising 95 percent Vistanex LMpolyisobutylene adhesive by weight of matrix 44 mixed with 5 percentsubstantially pure CBD by weight of matrix 44. A second device issimilarly constructed, but the amount of CBD in the matrix 44 is 10percent by weight of the matrix 44, and the amount of Vistanex LM is 90percent by weight of the matrix 44. A third patch is constructed using aDuroTak 87-2516 adhesive in an amount of 90 percent by weight of matrix44 and 10 percent CBD by weight of matrix 44, and a fourth patch isconstructed using a BIO PSA 7-4302 adhesive in an amount of 95 percentby weight of matrix 44 and 5 percent CBD by weight of matrix 44. Asindicated in FIG. 7, the Vistanex LM/10 percent CBD device providessuperior CBD transfer through the epidermis relative to the three otherdevices.

EXAMPLE 6

Three monolithic devices are constructed similar to those of Example 5.However, instead of pure CBD, a cannabis extract oil comprising 45.3percent CBD and 33.5% THC is mixed with the adhesive to form theadhesive matrix 44. In each device, the amount of oil in the matrix 44is 25 percent by weight of the matrix 44. The matrix 44 in the firstdevice comprises 75 percent by weight BIO PSA 7-4302. The matrix 44 inthe second device comprises 75 percent by weight Vistanex LM, and thematrix 44 in the third device comprises 75 percent by weight DuroTak87-2516. As indicated in FIG. 8, the devices with a PIB (Vistanex LM)and amine-compatible silicone adhesive (BIO PSA 7-4302) providesignificantly superior CBD transfer through the skin as compared to theacrylate (DuroTak 87-2516) adhesive.

Notably, from a 20 cm² reservoir device using a liquid carriercomprising ethanol and a CBD concentration of 10 weight percent (where20 cm²is the skin contact area), the expected daily dose of CBD is 30mg, which is six times higher than the expected dose from a monolithicpatch of the same skin contact area.

Accordingly, it is to be understood that the embodiments of theinvention herein described are merely illustrative of the application ofthe principles of the invention. Reference herein to details of theillustrated embodiments is not intended to limit the scope of theclaims, which themselves recite those features regarded as essential tothe invention.

What is claimed is:
 1. A transdermal patch formulation with CBD in PIB adhesive, from 1% to 30% and Vitamin C Palmitate.
 2. A transdermal patch formulation with CBD PIB adhesive with CBD concentration in solid adhesives from 1% to 30% and penetration enhancers in range of 0% to 10%, the CBD being crystalline CBD, further comprising <5% terpenes transmitted to skin.
 3. A method of transdermally delivering cannabidiol (CBD) to a person, comprising: providing a device housing at least one of a liquid saturated matrix and a saturated alcohol solution; removing the release liner from the first side of the porous, hydrophilic membrane; contacting the first side of the porous, hydrophilic membrane with the person's skin; and maintaining the device in contact with the person's skin for a period of lime sufficient to deliver the therapeutically effective amount of cannabidiol to the patient.
 4. A device for the transdermal delivery of cannabidiol (CBD), comprising: a backing; a mixture of an adhesive and a therapeutically effective amount of cannabidiol coated on the backing, wherein the mixture includes at least one of tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THC-a), cannabinol (CBN), and cannabichromene (CBC), vitamin B12, Terpenes and Beta-carylophenol; wherein the adhesive comprises an amine-compatible silicone adhesive and the mixture has a first surface adhered to the backing and a second, skin-adhering surface; a release liner removably attached to the second, skin adhering surface of the mixture.
 5. The device of claim 4, wherein the amine-compatible silicone adhesive comprises trimethylsiloxy and groups that are substantially non-reactive with amines.
 6. The device of claim 4, wherein the amine-compatible silicone adhesive comprises a trimethylsiloxy end-capped reaction product of a silanol endblocked polydimethylsiloxane with a silicate resin.
 7. The device of any of claim 4, wherein the adhesive has a viscosity ranging from about 1000 mPa-s to about 1800 mPa-s at a temperature of 20° C.
 8. A device for the transdermal delivery of cannabidiol (CBD), comprising: a backing; a release liner; a mixture of an adhesive and a therapeutically effective amount of cannabidiol coated on the release liner, wherein the mixture includes tetrahydrocannabinol (THC), tetrahydrocannabinolic acid (THC-a), cannabinol (CBN), and cannabichromene (CBC); wherein the adhesive comprises a polyisobutylene adhesive having a viscosity-average molecular weight ranging from about 30,000 Daltons to about 70,000 Daltons, and the mixture has a first surface adhered to the backing and a second, skin-adhering surface to which the release liner is removably adhered.
 9. The device of claim 8, wherein the adhesive has a viscosity at 20° C., ranging from about 1000 mPa-s to about 3000 mPa-s.
 10. A device of claim 9, wherein the mixture comprises a rosin.
 11. The device of claim 10, wherein the mixture comprises one or more non-cannabinoid terpenes.
 12. The device of claim 11, wherein the mixture comprises a rosin and one or more non-cannabinoid terpenes.
 13. The device of claim 12, wherein the mixture further comprises an adhesion/viscosity modifier comprises a mineral oil having a molecular weight of from about 350 to about 450 Daltons.
 14. The device of claim 12, wherein the mixture further comprises adhesion/viscosity modifier comprises a silicone fluid having a kinematic viscosity at 20° C. ranging from about 100 cSt to about 1000 cSt.
 15. The device of claim 14, wherein the silicone fluid is a hydroxyl end-capped polydimethylsiloxane fluid is a hydroxyl end-capped polydimethylsiloxane.
 16. The transdermal reservoir patch of claim 4, wherein Vitamin B12 is delivered in the presence of at least moiety selected from the group of THC, CBD and Terpenes.
 17. The transdermal reservoir patch of claim 4, further comprising at least one mechanism of CBD and THC delivery from liquid saturated matrix (E+OH+water); and use of hemp oil in delivering CBD from saturated alcohol solution, because of being too viscous for use with the saturated liquid matrix.
 18. The transdermal reservoir patch further comprising Vitamin C Palmitate. 